tbuckley/cabot-search huggingface dataset:
Abstract 4246: ABL103, A novel T-cell engaging bispecific antibody, exhibits potent <i>in vitro</i> and <i>vivo</i> antitumor activity and low toxicity via B7-H4 dependent 4-1BB activation in tumor microenvironment
Authors: Kyungjin Park, Yangsoon Lee, Saeyi Lim, Kyeongsu Park, Eunjung Kim, Hanbyul Lee, Jiseon Yoo, Youngdon Pak, Yeunju Kim, Minji Ko, Jonghwa Won
Journal: Cancer Research (2022)

Abstract B7-H4 (B7x, VTCN1), a member of the B7-family, is overexpressed in majority of cancer patients with ovarian, endometrial and breast cancers. B7-H4 expression was also observed in tumor associated macrophages and implicated as an immune checkpoint regulating T cell responses. Although B7-H4 expression in normal tissues is quite limited, tumor-specific immune response by ABL103 would minimize potential adverse effects. ABL103, B7-H4 Grabody-T, is a First-in Class bispecific antibody targeting B7-H4 and 4-1BB and augments T cell function by a dual mechanism, i.e., 1) blocks the B7-H4 mediated T cell inhibition, and 2) elicits superior T cell activation through B7-H4-dependent 4-1BB clustering. Our data showed that simultaneous binding of B7-H4 and 4-1BB by ABL103 led to potent in vitro T cell activation only in the presence of B7-H4 expressing tumor cells. In the established tumor model, ABL103 potently inhibited tumor progression in a dose-dependent manner and showed higher rate of complete remission (CR) at 2 and 10 mg/kg dose groups. Moreover, mice were protected from the tumor re-challenge 3 months after cessation of ABL103 treatment, suggesting long-term memory has been established. In 4-week pilot tox study using cynomolgus monkeys, ABL103 was tolerable up to 100 mg/kg dosed weekly with no ABL103-related toxicity observations. To understand the relationship of target expression, expression of B7-H4, CD4, CD8, PD-L1, and 4-1BB was examined in 142 ovarian cancer patient biopsies. About 83% of ovarian cancer patient tissues showed B7-H4 positive staining and 62% of them showed strong positive. In addition, the staining of 4-1BB as well as CD4 and CD8 T cells were observed in both tumor nest and stroma, suggesting that cross-linking of B7-H4 and 4-1BB is feasible in tumor microenvironment. Overall, ABL103 has a strong in vitro and vivo anti-tumor activity and good safety profile via B7-H4-dependent 4-1BB activation. This strongly suggests ABL103 is a promising therapeutic agent potentially benefitting patients with B7-H4 overexpression. Citation Format: Kyungjin Park, Yangsoon Lee, Saeyi Lim, Kyeongsu Park, Eunjung Kim, Hanbyul Lee, Jiseon Yoo, Youngdon Pak, Yeunju Kim, Minji Ko, Jonghwa Won. ABL103, A novel T-cell engaging bispecific antibody, exhibits potent in vitro and vivo antitumor activity and low toxicity via B7-H4 dependent 4-1BB activation in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4246.
Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus
Authors: Annalisa Schiepatti, David S Sanders, Paola Baiardi, Giacomo Caio, Carolina Ciacci, Katri Kaukinen, Benjamin Lebwohl, Daniel Leffler, Georgia Malamut, Joseph A Murray, Kamran Rostami, Alberto Rubio-Tapia, Umberto Volta, Federico Biagi
Journal: Gut (2022)

Differential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty.An international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted.Chronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes.This paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults.
Abstract 3179: Tumor educated lung epithelial cells promote osteosarcoma metastasis and chemotherapy resistance by inducing integrin dependent fibronectin fibrillogenesis
Authors: James Brandon Reinecke, Amy Gross, Maren Cam, Ryan Roberts
Journal: Cancer Research (2022)

Abstract Metastasis is the leading cause of cancer related deaths for patients with solid tumors. While tumor genomic evolution is one possible mechanism whereby cancer cells acquire chemotherapy resistance during the metastatic process, increasing evidence demonstrates that non-cancerous cells within the secondary organ have crucial roles in mediating metastasis and therapy resistance. Therefore, disrupting tumor-stromal cell interactions is an exploitable therapeutic strategy to improve outcomes. Unfortunately, mechanistic insight into tumor-stromal interactions is limited for most cancers. Osteosarcoma, an aggressive bone tumor that primarily afflicts children and young adults, displays an overwhelming propensity for metastasis to the lungs, with overall survival plummeting to less than 20% at 5 years upon lung metastasis. Why osteosarcoma displays tropism for the lung and how it educates the lung to promote tumor growth in a vastly different microenvironment from the primary tumor remains poorly understood. In this study, we utilized single-cell RNA sequencing to define the cellular and molecular landscape of osteosarcoma metastases in immunocompetent mouse models. We unexpectedly found that alveolar epithelial cells are the most prominent non-immune stromal component within lung metastases. Not only are they present in significant numbers in lung metastases compared to unaffected lung, our molecular analysis demonstrated that tumor associated epithelial cells acquire a pro-fibrosis ‘wound-like’ phenotype, which was also observed in human metastasis samples. Furthermore, utilizing human and mouse culture systems, we found that osteosarcoma cells directly reprogramed epithelial cells through secretion of growth factors and cytokines such as FGF7 and IL6. These profibrotic epithelial cells in turn induced osteosarcoma cells to generate a complex, beta-1integrin (ITGB1)- dependent fibronectin matrix. The epithelial induced fibronectin matrix promoted osteosarcoma invasion and chemotherapy resistance. Accordingly, inhibition of ITGB1 sensitized osteosarcoma cells to chemotherapy. Collectively our results demonstrate that osteosarcoma cells educate the lung microenvironment into a ‘pro-wound’, pro-fibrosis state that is conducive to osteosarcoma lung colonization. Disruption of the lung metastatic niche is a promising therapeutic target for sensitizing osteosarcoma cells to chemotherapy. Citation Format: James Brandon Reinecke, Amy Gross, Maren Cam, Ryan Roberts. Tumor educated lung epithelial cells promote osteosarcoma metastasis and chemotherapy resistance by inducing integrin dependent fibronectin fibrillogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3179.
Abstract 1296: MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells
Authors: Emeric Limagne, Lisa Nuttin, Marion Thibaudin, Elise Jacquin, Romain Aucagne, Marjorie Bon, Elise Ballot, Solène Revy, Robby Barnestein, Caroline Truntzer, Valentin Derangère, Jean-David Fumet, Rébé Cédric, Pierre-Simon Bellaye, Coureche-Guillaume Kaderbhai, Aodrenn Spill, Bertrand Collin, Mary Callanan, Aurélie Lagrange, Laure Favier, Bruno Coudert, Laurent Arnould, Sylvain Ladoire, Bertrand Routy, Philippe Joubert, François Ghiringhelli
Journal: Cancer Research (2022)

Abstract Chemotherapy with anti PD-1/PD-L1 mAb has become the standard of care for patients with metastatic non-small cell lung cancer (NSCLC). Using lung tumor models, where pemetrexed-platinum chemotherapy (PEM/CDDP) remains unable to synergize with immune checkpoint inhibitors (ICI), we linked failure of this treatment with its inability to induce CXCL10 expression and CD8+ T cell recruitment. Using drug screening, we showed that combining a MEK inhibitor (MEKi) with PEM/CDDP triggers CXCL10 secretion by cancer cells and CD8+ T cell recruitment, and restores ICI efficacy. PEM/CDDP plus MEKi promotes optineurin (OPTN)-dependent mitophagy, resulting in CXCL10 production in a mitochondrial DNA and TLR9-dependent manner. TLR9 or autophagy/mitophagy processes genetic inactivation of abort the antitumor efficacy of PEM/CDDP plus MEKi/anti PD-L1 therapy. In human NSCLC, high OPTN, TLR9 and CXCL10 expression is associated with better response to ICI. Our results underline the role of TLR9 and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy. Citation Format: Emeric Limagne, Lisa Nuttin, Marion Thibaudin, Elise Jacquin, Romain Aucagne, Marjorie Bon, Elise Ballot, Solène Revy, Robby Barnestein, Caroline Truntzer, Valentin Derangère, Jean-David Fumet, Rébé Cédric, Pierre-Simon Bellaye, Coureche-Guillaume Kaderbhai, Aodrenn Spill, Bertrand Collin, Mary Callanan, Aurélie Lagrange, Laure Favier, Bruno Coudert, Laurent Arnould, Sylvain Ladoire, Bertrand Routy, Philippe Joubert, François Ghiringhelli. MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1296.
Abstract 5147: The prion-like protein doppel as a seurm biomarker for epithelial ovarian cancer
Authors: Xiaojun Zhang, Bowon Kang, Mazharul Karim, Jianying Zhang, Jae Yun Song, In-San Kim, Taslim A. Al-Hilal
Journal: Cancer Research (2022)

Abstract Ovarian cancer has a dire prognosis with an overall 5-year survival rate of ~40%, whereas stage III and IV has a survival rate of only 3-19%. Failure to detect early contributes highly to the poor survival rate of ovarian cancer. Thus, early detection of EOCs is likely to translate into mortality benefit. Two tests used clinically to detect ovarian cancer are serum cancer antigen-125 (CA-125) and transvaginal ultrasound. Both have limitations of specificity and sensitivity. CA-125 along with other biomarkers that are in clinical trials express both in the ovaries and serum of healthy females. Thus, the specific detection among cancer-free controls versus ovarian cancer cases remains highly variable. We hypothesize to assess the Doppel (PRND gene) as a serum biomarker in the detection of epithelial ovarian cancers (EOC) at the early stages. Doppel, a prion-like protein first identified in 1996, is known to express in testis and appears to regulate male fertility. Previously, we and others reported that Doppel is a highly specific tumor endothelium marker. In this study, to validate the potential of Doppel as an EOC serum biomarker, using ELISA, we detected Doppel concentration in the sera of 76 sera samples from patients with stage and histopathology information, and in 18 normal human sera (NHS). Doppel level was significantly higher in sera of EOC patients than NHS (0.720 vs 6.653 ng/ml, p&amp;lt;0.0001); 72 out of 76 patients were positive for Doppel expression (cut off value was calculated as Mean+3×SEM = 1.296 ng/mL) while only 3 out of 18 cases were positive for NHS. Receiver operating characteristic (ROC) analysis showed that Doppel can differentiate EOC patients from normal individuals with AUC of 0.957, sensitivity of 90.8%, and specificity of 90%. Doppel was markedly higher in all stages of EOC than NHS (Stage I, 6.261 ng/mL; Stage II, 8.045 ng/ml; Stage III, 7.040 ng/mL; and Stage IV, 5.726 ng/ml vs NHS 0.720 ng/ml; p&amp;lt;0.001). Interestingly, serum Doppel level was higher among EOC of serous adenocarcinoma (7.020 ng/mL; n = 39), mucinous (10.780 ng/mL; n = 8), and endometroid (7.295 ng/mL; n = 7) than clear cell (3.114 ng/mL; n = 7) or other types (4.855 ng/mL; n = 15). Together, our study showed the potential of Doppel as a serological biomarker for EOC detection. Citation Format: Xiaojun Zhang, Bowon Kang, Mazharul Karim, Jianying Zhang, Jae Yun Song, In-San Kim, Taslim A. Al-Hilal. The prion-like protein doppel as a seurm biomarker for epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5147.
Abstract 663: Systemic targeting of therapeutic RNA to cancer via a novel, cell-penetrating and nucleic acid binding, monoclonal antibody
Authors: Elias Quijano, Diana Martinez Saucedo, Minsoo Khang, Yanfeng Liu, Dale Ludwig, Bruce C. Turner, Stephen Squinto, Ranjit Bindra, W. Mark Saltzman, Luisa Escobar-Hoyos, Peter M. Glazer
Journal: Cancer Research (2022)

Abstract There is intense interest in the development of nucleic acid ligands for immune stimulation of the tumor microenvironment via pattern recognition receptors (PRRs), particularly for the treatment of “cold” tumors. However, delivery of these ligands in a tumor-specific manner to avoid systemic toxicity has been a challenge. Many current efforts rely on direct intra-tumoral injection of RNAs or other stimulatory immune ligands, which is therapeutically sub-optimal, especially for metastatic disease. Here we report studies evaluating the utility of a lupus-derived, cell-penetrating antibody, to deliver nucleic acids to tumors in vivo. This antibody, a modified version of 3E10-D31N, designated GMAB, forms non-covalent complexes with RNAs and can mediate highly specific delivery into tumors via intravenous injection by targeting the nucleoside transporter ENT2, which is highly expressed in tumor cells. Studies with labeled RNAs showed tumor specific delivery and functional expression by imaging, with minimal delivery to healthy tissues. Following these proof-of-concept studies, we investigated whether our antibody could be used to deliver RIG-I agonists to tumors. Using a known agonist of RIG-I, 3p-hpRNA, we demonstrated single agent activity of our GMAB/RNA complexes in multiple tumor models, including a mouse model of melanoma (B16) and an orthotopic model of pancreatic cancer (KPC). Measuring 3p-hpRNA by RT-PCR, there was a 1000X fold difference in RNA uptake in KPC tumor cells relative to CD45+ cells isolated from tumors. In addition, synergy between our GMAB/RNA complexes and anti-PD-1 was additionally observed in mouse models of breast (EMT6) and colon (MC38) cancer. Given the expression of ENT2 along the blood brain barrier (BBB), we demonstrate single agent activity of our GMAB/RNA complexes in an orthotopic mouse model of medulloblastoma, resulting in suppression of tumor growth and spinal metastases. Together, these studies demonstrate that the GMAB antibody can 1) localize to orthotopic and flank tumor models, 2) cross the BBB, and 3) deliver RNA payloads to tumors, providing a novel platform for delivery of immunogenic RNAs, as well as mRNAs and siRNAs, directly to tumors with high specificity following systemic administration. Citation Format: Elias Quijano, Diana Martinez Saucedo, Minsoo Khang, Yanfeng Liu, Dale Ludwig, Bruce C. Turner, Stephen Squinto, Ranjit Bindra, W. Mark Saltzman, Luisa Escobar-Hoyos, Peter M. Glazer. Systemic targeting of therapeutic RNA to cancer via a novel, cell-penetrating and nucleic acid binding, monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 663.
Abstract 5362: Targeting PIK3CB in glioblastoma
Authors: Marc R. Fromherz, Kevin J. Pridham, Zhi Sheng
Journal: Cancer Research (2022)

Abstract Background: Glioblastoma (GBM) is the most common and one of the most lethal malignant brain tumors in existence. The poor prognosis of this disease is due in part to tumor recurrence and temozolomide (TMZ) resistance, for which PI3K/AKT pathway overactivation has been implicated. Our work is to demonstrate that p110β inhibition could represent a therapeutic target in sensitizing recurrent tumors to TMZ therapy, and demonstrate the utility of personalized GBM treatments. Objective: We aim to develop a more effective treatment for TMZ resistant GBM patients. We hypothesize that a p110β inhibitor will sensitize resistant GBM cell lines to TMZ therapy. We intend to support this hypothesis by demonstrating that the p110β inhibitor TGX-221 in combination with TMZ will provide a significantly greater level of cytotoxicity on TMZ resistant GBM cell lines than TGX-221 or TMZ monotherapy alone. We also intend to provide further evidence for this therapy by utilizing it to overcome TMZ resistance in glioblastoma stem cells (GSC’s). Methods: We compared the cytotoxicity of TMZ, TGX-221, and a TMZ/TGX-221 combination therapy on p110β-high/TMZ resistant and p110β-low/TMZ sensitive GBM cell lines. Cell viability was determined using the MTS assay. We then tested these reagents on normal human astrocytes to determine any potential dose-limiting off-target effects. Lastly, we tested these reagents using human-derived GSC’s. Results: A statistically significant difference (p &amp;lt; 0.01) in cell viability was found using the TMZ/TGX-221 combination therapy as compared to either TMZ or TGX-221 alone in our TMZ resistant SF295 cells, and a significant different was found between the combination therapy and TMZ monotherapy in our TMZ resistant U87MG cells. No significant difference was found between treatments in our TMZ sensitive A172 cells or normal human astrocytes. Conclusions: The results of our GBM cell line experiments provide support that combination TMZ/TGX-211 is superior in cytotoxicity to either monotherapy alone in TMZ resistant cell lines. This indicates that TGX-211, through p110β inhibition, is able to sensitize resistant cell lines to TMZ therapy. More experiments are ongoing to determine if this effect will also be demonstrated in human-derived GSC’s. Citation Format: Marc R. Fromherz, Kevin J. Pridham, Zhi Sheng. Targeting PIK3CB in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5362.
Epigenetic reactivation of transcriptional programs orchestrating fetal lung development in human pulmonary hypertension
Authors: Prakash Chelladurai, Carsten Kuenne, Alice Bourgeois, Stefan Günther, Chanil Valasarajan, Anoop V. Cherian, Robbert J. Rottier, Charlotte Romanet, Andreas Weigert, Olivier Boucherat, Christina A. Eichstaedt, Clemens Ruppert, Andreas Guenther, Thomas Braun, Mario Looso, Rajkumar Savai, Werner Seeger, Uta-Maria Bauer, Sébastien Bonnet, Soni Savai Pullamsetti
Journal: Science Translational Medicine (2022)

Phenotypic alterations in resident vascular cells contribute to the vascular remodeling process in diseases such as pulmonary (arterial) hypertension [P(A)H]. How the molecular interplay between transcriptional coactivators, transcription factors (TFs), and chromatin state alterations facilitate the maintenance of persistently activated cellular phenotypes that consequently aggravate vascular remodeling processes in PAH remains poorly explored. RNA sequencing (RNA-seq) in pulmonary artery fibroblasts (FBs) from adult human PAH and control lungs revealed 2460 differentially transcribed genes. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed extensive differential distribution of transcriptionally accessible chromatin signatures, with 4152 active enhancers altered in PAH-FBs. Integrative analysis of RNA-seq and ChIP-seq data revealed that the transcriptional signatures for lung morphogenesis were epigenetically derepressed in PAH-FBs, including coexpression of T-box TF 4 ( TBX4 ), TBX5 , and SRY-box TF 9 ( SOX9 ), which are involved in the early stages of lung development. These TFs were expressed in mouse fetuses and then repressed postnatally but were maintained in persistent PH of the newborn and reexpressed in adult PAH. Silencing of TBX4 , TBX5 , SOX9 , or E1A-associated protein P300 ( EP300 ) by RNA interference or small-molecule compounds regressed PAH phenotypes and mesenchymal signatures in arterial FBs and smooth muscle cells. Pharmacological inhibition of the P300/CREB-binding protein complex reduced the remodeling of distal pulmonary vessels, improved hemodynamics, and reversed established PAH in three rodent models in vivo, as well as reduced vascular remodeling in precision-cut tissue slices from human PAH lungs ex vivo. Epigenetic reactivation of TFs associated with lung development therefore underlies PAH pathogenesis, offering therapeutic opportunities.
Pre-existing adaptive immunity to the RNA-editing enzyme Cas13d in humans
Authors: Xin-Zi Emily Tang, Shu Xuan Tan, Shawn Hoon, Gene W. Yeo
Journal: Nature Medicine (2022)

Abstract RNA-guided RNA-targeting nucleases, such as CRISPR–Cas13 proteins, have therapeutic potential for gene editing. Among Cas13d enzymes, Cas13d from the bacteria Ruminococcus flavefaciens (RfxCas13d) is of particular interest owing to its small size and high specificity. However, the existence of pre-existing immunity against RfxCas13d is unclear. In this study, we evaluated antibody and T cell responses to RfxCas13d in healthy donors using ELISA and T cell culture assays. We found RfxCas13d-reactive antibodies and CD4 and CD8 T cell responses in most donors, comparable to responses against Cas9 proteins from Staphylococcus aureus (SaCas9) and Streptococcus pyogenes (SpCas9). RfxCas13d-responding T cells could produce the inflammatory cytokines IFN-γ, TNF-α and IL-17. These findings should be taken into consideration in the development of RfxCas13d for therapy.